Temozolomide Chronotherapy for High Grade Glioma

A Randomized Feasibility Study Evaluating Temozolomide Chronotherapy for High Grade Glioma

Temozolomide (TMZ) is the chemotherapy drug approved by the FDA to increase survival in glioblastoma (GBM) patients beyond surgical resection and radiation therapy alone. Give its activity in astrocytomas, TMZ is commonly used in grade III anaplastic astrocytoma (AA) as well. Both grade III AA and grade IV GBM are high grade gliomas (HGG). The short half-life of this drug and known oscillations in DNA damage repair make it an ideal candidate for chronotherapy.

Chronotherapy is the improvement of treatment outcomes by minimizing treatment toxicity and maximizing efficacy through delivery of a medication according to the timing of biological rhythms within a patient. Chronotherapy has improved outcomes through the reduction of side effects and increase in anti-tumor activity for a variety of cancers, but has never been applied to the treatment of gliomas.

Based on the preliminary preclinical data for chronotherapeutic TMZ treatment of intracranial glioma xenografts and the success of chronotherapy in the treatment of other cancers, the invesitgators hypothesize that the timing of TMZ treatment will alter its efficacy and toxicity.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioma; Glioblastoma Multiforme
• Intervention / Treatment: Drug: Temozolomide; Other: Functional Assessment of Cancer Therapy - Brain; Other: ActTrust Condor Instrument Watch

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Newly diagnosed and recurrent high grade gliomas (WHO grades III & IV) and high risk WHO grade II gliomas who are to begin treatment with monthly high dose temozolomide therapy.
• Scheduled to receive adjuvant temozolomide therapy after having completed concurrent temozolomide and radiation therapy.
• At least 18 years of age.
• Karnofsky performance status ≥ 60%
• Ability to understand and willingness to sign an IRB approved written informed consent document

Exclusion Criteria:.

-Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Temozolomide morning; Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m^2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the morning (before 10:00).; FACT-Br quality of life at baseline, at the beginning of each cycle of chemotherapy, and 1 month after the final chemotherapy treatment	Drug: Temozolomide; -Given standard of care; Other Names: Temodar; Other: Functional Assessment of Cancer Therapy - Brain; 23-item questionnaire that can be completed in 5 to 10 minutes with little or no assistance in patients who are not neurologically incapacitated. This brain subscale is usually used along with the core (general) questionnaire [2] that includes 27 items.; Patients rate all 5 items using a five-point Likert scale ranging from 0 "not at all" to 4 "very much." Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items); The sleep portion of this questionnaire consists of 17 questions about sleeping patterns and the ability to rate severity of insomnia.; Other Names: FACT-Br; Other: ActTrust Condor Instrument Watch; -Will be required to wear 24 hours per day and will only be removed at specified data collection time points
Experimental: Arm 2: Temozolomide evening; Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the evening (after 20:00).; FACT-Br quality of life at baseline, at the beginning of each cycle of chemotherapy, and 1 month after the final chemotherapy treatment	Drug: Temozolomide; -Given standard of care; Other Names: Temodar; Other: Functional Assessment of Cancer Therapy - Brain; 23-item questionnaire that can be completed in 5 to 10 minutes with little or no assistance in patients who are not neurologically incapacitated. This brain subscale is usually used along with the core (general) questionnaire [2] that includes 27 items.; Patients rate all 5 items using a five-point Likert scale ranging from 0 "not at all" to 4 "very much." Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items); The sleep portion of this questionnaire consists of 17 questions about sleeping patterns and the ability to rate severity of insomnia.; Other Names: FACT-Br; Other: ActTrust Condor Instrument Watch; -Will be required to wear 24 hours per day and will only be removed at specified data collection time points

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of patient treatment compliance as measured by at least 80% compliance with assigned administration time	Compliance is defined as no more than one of five doses of temozolomide per cycle taken outside of the assigned administration time.	Completion of treatment (estimated to be 6 months)
Duration of response	Response and progression will be evaluated in this study using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline [JCO 28(11): 1963-1972, 2010].; The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).	Through completion of follow-up (estimated to be 30 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients experiencing grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia and anemia in each group as measured by standard blood draws	Lymphopenia grade 3 is <500-200/mm3 and grade 4 is <200/mm3; Leukopenia grade 3 is <2000-1000/mm3 and grade 4 is <1000/mm3; Neutropenia grade 3 is <1000-500/mm3 and grade 4 is <500/mm3; Thrombocytopenia grade 3 is <50,000-25,000/mm3 and grade 4 is <25,000/mm3; Anemia grade 3 is <8.0-6.5 g/dL and grade 4 is <6.5 g/dL	Completion of treatment (estimated to be 6 months)
Quality of life as measured by FACT-Br score		1 month after completion of treatment (estimated to be 7 months)
Progression-free survival (PFS)	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.	Through completion of follow-up (estimated to be 30 months)
Overall survival		Through completion of follow-up (estimated to be 30 months)
Comparison of the level of sleep disruption in sleep-wake cycles of participants receiving temozolomide in the morning versus participants receiving temozolomide in the evening	The data will be collected through the ActTrust Condor Instrument Watch and the Sleep Questionniare.; The qualitative data (sleep questionnaire) will be used with quantitative data (collected via the ActTrust watch) to assess the level of sleep disruption in sleep/wake cycles	Through 1 month after completion of treatment (estimated to be 7 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Milan Chheda, M.D., Washington University School of Medicine

Publications and helpful links

General Publications

• Damato AR, Katumba RGN, Luo J, Atluri H, Talcott GR, Govindan A, Slat EA, Weilbaecher KN, Tao Y, Huang J, Butt OH, Ansstas G, Johanns TM, Chheda MG, Herzog ED, Rubin JB, Campian JL. A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma. Neurooncol Pract. 2022 Jan 31;9(3):193-200. doi: 10.1093/nop/npac003. eCollection 2022 May.

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2016
• Primary Completion (Estimated): July 14, 2024
• Study Completion (Estimated): July 14, 2024

Study Registration Dates

• First Submitted: May 20, 2016
• First Submitted That Met QC Criteria: May 20, 2016
• First Posted (Estimated): May 24, 2016

Study Record Updates

• Last Update Posted (Estimated): October 10, 2023
• Last Update Submitted That Met QC Criteria: October 9, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: 201605081

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No